Abstract
The inability of the immune system to recognize and kill malignant plasma cells in patients with multiple myeloma (MM) has been attributed in part to the ineffective activation of natural killer (NK) cells. In order to activate and target NK cells to the malignant cells in MM we designed a novel recombinant bispecific protein (ULBP2-BB4). While ULBP2 binds the activating NK receptor NKG2D, the BB4 moiety binds to CD138, which is overexpressed on a variety of malignancies, including MM. ULBP2-BB4 strongly activated primary NK cells as demonstrated by a significant increase in interferon-gamma (IFN-gamma) secretion. In vitro, ULBP2-BB4 enhanced the NK-mediated lysis of 2 CD138+ human MM cell lines, U-266 and RPMI-8226, and of primary malignant plasma cells in the allogenic and autologous setting. Moreover, in a nude mouse model with subcutaneously growing RPMI-8226 cells, the cotherapy with ULBP-BB4 and human peripheral blood lymphocytes abrogated the tumor growth. These data suggest potential clinical use of this novel construct in patients with MM. The use of recombinant NK receptor ligands that target NK cells to tumor cells might offer new approaches for other malignancies provided a tumor antigen-specific antibody is available.
MeSH terms
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Animals
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Antibodies, Monoclonal / genetics
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology*
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COS Cells
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Carrier Proteins / genetics
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Carrier Proteins / immunology
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Carrier Proteins / pharmacology*
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Cell Line, Tumor
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Chlorocebus aethiops
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Drug Delivery Systems / methods
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GPI-Linked Proteins
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Histocompatibility Antigens Class I / genetics
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Histocompatibility Antigens Class I / immunology
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Histocompatibility Antigens Class I / pharmacology*
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Humans
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Immunoglobulin Variable Region / genetics
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Immunoglobulin Variable Region / immunology
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Immunoglobulin Variable Region / pharmacology*
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Intercellular Signaling Peptides and Proteins
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Killer Cells, Natural / immunology*
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Lymphocyte Activation / drug effects*
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Lymphocyte Activation / immunology
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Membrane Glycoproteins / immunology
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Mice
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Mice, Nude
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / immunology
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NK Cell Lectin-Like Receptor Subfamily K
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Neoplasm Transplantation
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Proteoglycans / immunology
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Receptors, Immunologic / immunology
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Receptors, Natural Killer Cell
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology
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Recombinant Fusion Proteins / pharmacology
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Syndecan-1
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Syndecans
Substances
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Antibodies, Monoclonal
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Carrier Proteins
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GPI-Linked Proteins
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Histocompatibility Antigens Class I
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Immunoglobulin Variable Region
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Intercellular Signaling Peptides and Proteins
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KLRK1 protein, human
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Klrk1 protein, mouse
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Membrane Glycoproteins
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NK Cell Lectin-Like Receptor Subfamily K
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Proteoglycans
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Receptors, Immunologic
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Receptors, Natural Killer Cell
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Recombinant Fusion Proteins
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SDC1 protein, human
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Sdc1 protein, mouse
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Syndecan-1
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Syndecans
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ULBP2 protein, human